Solid Forms of the Magnesium Salt of S-Omeprazole and Processes for Their Preparation

ABSTRACT

New solid forms of the active ingredient magnesium salt of S-omeprazole, obtainable by a preparation process including: a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that includes a mixture of methanol/water with an amount of water equal to or greater than about 0.01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the prior operation; c) separating the free organic solvent from the magnesium salt of S-omeprazole obtained or, alternatively, separating both the free solvent and the solvation solvent. The new solid forms are obtained by a reproducible and robust process, with high yield and elevated optical purity, which is useful for the preparation of pharmaceutical products that contain said active ingredient.

The present invention relates to new solid forms of the magnesium salt of S-omeprazole and to processes for their preparation, as well as intermediates for their preparation.

BACKGROUND ART

The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, which has the generic name omeprazole, was described for the first time in the document EP 5.129-A. Omeprazole is a sulphoxide that contains an asymmetric center in the sulphur atom, and therefore exists as a racemic mixture of two enantiomers, R-omeprazole and S-omeprazole. The R configuration corresponds to the (+)-enantiomer and the S configuration to the (−)-enantiomer.

Omeprazole is susceptible to degradation in acidic and neutral media. Its stability is also affected by other factors such as humidity, temperature and organic solvents. Certain salts of omeprazole are described in EP 124.495-A where it indicates that they are more stable during storage than the neutral form of omeprazole.

Omeprazole and its alkaline salts are effective inhibitors of gastric acid secretion and, therefore, are useful for the prevention and treatment of gastric acid-related disorders and inflammatory gastrointestinal diseases (e.g., gastric ulcer, duodenal ulcer, reflux esophagitis and gastritis). In addition, they can also be used for the treatment of other gastrointestinal disorders where a cytoprotectant and/or anti-gastric secretion effect is desired (e.g., in patients with gastrinomas, in patients with acute upper gastrointestinal hemorrhage, and in patients with a history of chronic and excessive alcohol consumption).

EP 652.872-A describes the magnesium salt of S-omeprazole, the formula of which is included below, and indicates that it possesses pharmacokinetic and metabolic properties that give it an improved therapeutic profile. There are other documents that describe different solid forms of magnesium salt of S-omeprazole. EP 984.957-A describes a trihydrate form of magnesium salt of S-omeprazole. WO 04/20436 describes a hydrate of magnesium salt of S-omeprazole in amorphous solid form. Finally, EP 1.375.497-A describes a magnesium salt of S-omeprazole with a grade of crystallinity of less than 67% and a magnesium salt of S-omeprazole with an amount of organic solvent of less than 7%.

The different solid forms of a pharmaceutically active ingredient can have different characteristics, and offer certain advantages, for example with regard to solubility or bioavailability. Thus, the discovery of new solid forms allows for improving the characteristics of the pharmaceutical formulations of the active ingredients, since some forms are more adequate for one type of formulation, and other forms for other different formulations. Furthermore, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferred, hence omeprazole is commercialized, for example, in the form of capsules and vials, and S-omeprazole as gastroresistant tablets. It is hence of interest to have new solid forms of magnesium salt of S-omeprazole.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, it is provided a solid form of magnesium salt of S-omeprazole that gives the X-ray diffractogram shown in FIG. 1. Said diffractogram differs from those of other forms of magnesium salt of S-omeprazole known in the state of the art. This new solid form of magnesium salt of S-omeprazole is characterized by exhibiting in the powder X-ray diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 20θ (°), which is shown in the following table: 2θ (°) d (Å) Intensity (%) 5.9 15.1 100 6.5 13.6  81 7.6 11.7  90 8.2 10.8  40

This form is essentially free of organic solvent, whether it be free or of solvation. By the expression “essentially free of organic solvent” it is understood that it complies with the relevant pharmaceutical specifications for the presence of solvents. By free solvent it is understood that it does not form part of the product's crystalline structure, and by solvation solvent it is understood that it is incorporated into the crystalline structure of the same.

X-ray diffractogram is obtained using a Debye-Scherrer INEL CPS120 geometry diffractometer at a Cu-Kα1 radiation (λ=1.5406 Å) and at a power of 40 kV-30 mA.

A second aspect of the present invention relates to a process for the preparation of the magnesium salt of S-omeprazole, essentially free of organic solvent, that comprises the following steps: a) crystallizing a magnesium salt of S-omeprazole from a solution of magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the previous step; and c) separating the solvent from the magnesium salt of S-omeprazole obtained.

Preferably, the amount of water of the solvent system is between 0.01 and 4 ml/g of the magnesium salt of S-omeprazole starting material. It is more preferred that the amount of water is between 0.01 and 2 ml/g of the magnesium salt of S-omeprazole starting material. More preferred yet is that the amount of water of the solvent system is between 0.01 and 0.5 ml/g of the magnesium salt of S-omeprazole starting material. Even more preferred is that the amount of water of the solvent system is between 0.01 and 0.1 ml/g of the magnesium salt of S-omeprazole starting material. The amount of water varies according to the dilution of the solution of the magnesium salt of S-omeprazole in the solvent system used and according to the solvents that form part of said solvent system, and can be added at the beginning or once the crystallization of the product has begun. This last possibility is preferably used when the amounts of water are in the upper range, preferably from 2 ml/g and up of magnesium salt of S-omeprazole.

The isolation of the product can be done by a conventional method such as filtration. In a preferred embodiment the separation of the solvent is done by suspension of the magnesium salt of S-omeprazole in water, followed by isolation of the magnesium salt of S-omeprazole obtained and subsequent drying. In general, the suspension of the magnesium salt in water is performed at a temperature between 2-30° C. and during 30-60 minutes. At higher temperatures the suspension time is less. In another preferred embodiment the separation of the solvent is done by drying at a temperature between 60-120° C.

In one particular embodiment of this preparation process, a cosolvent selected from (C₁-C₄)-alkyl esters and acetonitrile is added to the solution of the magnesium salt of S-omeprazole in methanol/water. Preferably, the cosolvent is selected from ethyl acetate or acetonitrile.

The magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent, can also be obtained from a methanol-solvated magnesium salt of S-omeprazole, through a process of desolvation. A preferred methanol_solvated magnesium salt of S-omeprazole exhibits a pattern of peaks in the X-ray diffractogram, expressed in 2 theta units in degrees,2θ (°), which is shown in the following table: 2θ (°) d (Å) Intensity (%) 5.6 15.9 69 6.5 13.7 61 7.3 12.1 100 8.0 11.1 15 10.6 8.4 10 10.8 8.2 11 11.3 7.9 13 12.6 7.0 21 13.3 6.7 10 13.8 6.4 15 14.7 6.0 13 15.3 5.8 10 16.4 5.4 13 16.8 5.3 21 17.5 5.1 26 17.8 5.0 14 18.3 4.9 14 18.8 4.7 15 19.1 4.7 23 19.6 4.5 23 20.1 4.4 18 20.4 4.4 26 21.7 4.1 12 21.9 4.1 13 22.1 4.0 14 23.4 3.8 16 24.2 3.7 16 24.8 3.6 16 25.2 3.5 15 25.3 3.5 15 26.2 3.4 11 27.1 3.3 12 28.3 3.2 9 29.1 3.1 9 29.3 3.1 10 31.7 2.8 10

In a preferred embodiment, the desolvation process is carried out by suspension in water, generally at a temperature between 2-30° C. for 30-60 minutes, followed by isolation of the obtained magnesium salt of S-omeprazole and by subsequent drying. In another preferred embodiment the desolvation process is performed by drying at a temperature between 60-120° C.

This methanol-solvated magnesium salt of S-omeprazole that acts as an intermediate for the preparation of the solid form, essentially free of organic solvent of the present invention, can be prepared by a process which comprises the following steps: a) crystallizing said magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water that is equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that is obtained in the first step; and c) drying the obtained magnesium salt of S-omeprazole at a temperature less than 60° C. The drying temperature is preferably room temperature.

Preferably, the amount of water of the solvent system is between 0.01 and 4 ml/g of the magnesium salt of S-omeprazole starting material. It is more preferred that the amount of water is between 0.01 and 2 ml/g of the magnesium salt of S-omeprazole starting material. More preferred yet is that the amount of water of the solvent system is between 0.01 and 0.5 ml/g of the magnesium salt of S-omeprazole starting material. Even more preferred is that the amount of water of the solvent system is between 0.01 and 0.1 ml/g of the magnesium salt of S-omeprazole starting material. The amount of water varies according to the dilution of the solution of the magnesium salt of S-omeprazole in the solvent system used and according to the solvents that form part of said solvent system, and can be added at the beginning or once the crystallization of the product has begun. This last possibility is preferably used when the amounts of water are in the upper range, preferably from 2 ml/g and up of magnesium salt of S-omeprazole.

In one particular embodiment of this preparation process, a cosolvent selected from the group consisting of (C₁-C₄)-alkyl esters and acetonitrile is added to the solution of the magnesium salt of S-omeprazole in methanol/water. Preferably, the cosolvent is selected from ethyl acetate or acetonitrile.

The most adequate conditions for carrying out said processes vary depending on the parameters considered by the expert in the art, such as, for example, the concentration of the starting material, temperature, the cosolvent used, and the like. These can be easily determined by said skilled person in the art by routine tests and with the help of the teachings of the examples given in this description.

According to an additional aspect of the present invention, a preparation process is provided that allows for the obtaining of solid forms of the magnesium salt of S-omeprazole that comprises the following steps: a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water that is equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the prior step; and c) separating the organic solvent from the obtained magnesium salt of S-omeprazole. Therefore, the present invention also includes any solid form of magnesium salt of S-omeprazole obtainable by this preparation process.

Another aspect of the present invention relates to a pharmaceutical composition that comprises as the active ingredient a therapeutically effective amount of the magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent, together with suitable pharmaceutically acceptable excipients or carriers.

An advantage of the solid forms of the present invention is that they have a high stability and physico-mechanical properties that allow for good manipulation for the preparation of solid pharmaceutical formulations. Another advantage of the solid forms of the present invention lies in the fact that they are obtained with high yields and elevated richness, that is, with a greater than 99% purity and with levels of sulphone and N-oxide sulphone—common impurities in the synthesis of prazoles that are difficult to eliminate—significantly inferior to the beginning levels, staying below 0.10%. Likewise they are obtained with an elevated optical purity, that is, with an enantiomeric excess (e.e.) equal to or greater than 99%, even when the starting material is an optically contaminated magnesium salt of S-omeprazole. Furthermore, the solid forms of the present invention have another additional advantage, given that their preparation process is reproducible and robust, and, therefore, easily industrializable.

Throughout the description and the claims the word “comprises” and its variants are not meant to exclude other technical characteristics, additives, components or steps. The summary of this application is included here for reference. For skilled persons in the art, other objects, advantages and characteristics of the invention can be deduced in part from the description and partly from the practice of the invention. The following examples are provided for illustrative means, and are not meant to be limiting of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray diffraction spectrum of the magnesium salt of S-omeprazole of the present invention, essentially free of organic solvent.

EXAMPLES Example 1 Preparation of a New Solid Form of the Methanol-Solvated Magnesium Salt of S-omeprazole

20 g of magnesium salt of S-omeprazole (90.6% ee; Karl-Fischer: 2.3%) were dissolved in 60 ml of methanol at room temperature. 300 ml of acetonitrile were added. The solid in suspension was filtered and dried at room temperature and at reduced pressure. 17 g of the title compound were obtained (85% of yield; 99.3% ee; 4.3% p/p of methanol by gas chromatography).

Example 2 Preparation of a New Solid Form of Magnesium Salt of S-omeprazole, Essentially Free of Organic Solvent

5.0 g of the magnesium salt of S-omeprazole obtained in Example 1 were dried at 70° C. and at reduced pressure, and 4.9 g of the title compound were obtained. The X-ray diffraction analysis gave the diffractogram shown in FIG. 1.

Example 3 Preparation of a New Solid Form of the Magnesium Salt of S-omeprazole, Essentially Free of Organic Solvent

10.0 g of the magnesium salt of S-omeprazole, obtained according to Example 1 from a magnesium salt of S-omeprazole of a richness of 97.7% a/a (N-oxide sulphone impurity: 0.6% a/a and sulphone impurity: 0.4% a/a), were suspended in 50 ml of water. It was left stirring for about 45 minutes at room temperature and then the solid in suspension was filtered. It was dried at 50° C. and at reduced pressure. 9.5 g of the title compound were obtained (95% of yield; richness: 99.7% a/a, N-oxide sulphone impurity: 0.02% a/a; sulphone impurity: 0.05% a/a). The X-ray diffraction analysis gave a diffractogram equal to the one shown in FIG. 1.

Example 4 Preparation of a New Solid Form of the Magnesium Salt of S-omeprazole, Essentially Free of Organic Solvent

15.0 g of a magnesium salt of S-omeprazole (90.6% ee; Karl-Fischer: 9.2%) were dissolved in 45 ml of methanol at room temperature. 270 ml of ethyl acetate were added. It was left stirring until the appearance of a solid in suspension. The solid was filtered and dried at 90° C. and at reduced pressure. 12.8 g of magnesium salt of S-omeprazole (85% of yield, 99.2% ee) were obtained, which gives an X-ray diffractogram equal to that shown in FIG. 1.

Example 5 Preparation of a New Solid Form of the Magnesium Salt of S-omeprazole, Essentially Free of Organic Solvent

2.0 g of the magnesium salt of S-omeprazole (Karl-Fischer: 2.3%) were dissolved in 6 ml of methanol. It was left stirring until the appearance of a solid in suspension. It was filtered, and dried at 70° C. and at reduced pressure. 1.2 g of magnesium salt of S-omeprazole (60% of yield) were obtained, which gives an X-ray diffractogram equal to that shown in FIG. 1.

Example 6 Preparation of a New Solid Form of the Magnesium Salt of S-omeprazole, Essentially Free of Organic Solvent

20.0 g of the magnesium salt of S-omeprazole (Karl-Fischer: 9.7%) were dissolved in 100 ml of methanol. 300 ml of acetonitrile and 40 ml of water were added. The solid in suspension was filtered and dried at 70° C. and reduced pressure. 12.7 g of magnesium salt of S-omeprazole (64% of yield) were obtained, which gives an X-ray diffractogram equal to that shown in FIG. 1. 

1. A solid form of the magnesium salt of S-omeprazole having an X-ray diffractogram comprising characteristic peaks of greatest intensity at approximately 5.9, 6.5, and 7.6 degrees 2 theta, without any other significant peak.
 2. Solid form of the magnesium salt of S-omeprazole according to claim 1, further characterized by an X-ray difractogram as in FIG.
 1. 3. A preparation process of the solid form of magnesium salt of S-omeprazole defined in claim 1, comprising the following operations: a) crystallizing a magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water about equal to or greater than 0.01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the prior operation; and c) separating the organic solvent from the magnesium salt of S-omeprazole obtained.
 4. A process according to claim 3, wherein the amount of water between about 0.01 and about 4 ml/g of the magnesium salt of S-omeprazole starting material.
 5. A process according to claim 4, wherein the amount of water is between about 0.01 and about 2 ml/g of the magnesium salt of S-omeprazole starting material.
 6. A process according to claim 5, wherein the amount of water is betweem about 0.01 and about 0.5 ml/g of the magnesium salt of S-omeprazole starting material.
 7. A process according to claim 6, wherein the amount of water is between about 0.01 and about 0.1 ml/g of the magnesium salt of S-omeprazole starting material.
 8. A process according to claim 3, wherein the separation of the organic solvent comprises the operations of suspension of the magnesium salt of S-omeprazole in water; isolation of the obtained magnesium salt of S-omeprazole; and subsequent drying.
 9. A process according to claim 3, wherein the separation of the solvent is carried out by drying at a temperature of between about 60 and about 120° C.
 10. A process according to claim 3, comprising the additional operation of adding a cosolvent selected from the group consisting of (C₁-C₄)-alkyl esters, ethyl acetate and acetonitrile to the solution of the magnesium salt of S-omeprazole in methanol/water.
 11. (canceled)
 12. (canceled)
 13. A preparation process of the magnesium salt of S-omeprazole as defined in claim 1, from a methanol-solvated magnesium salt of S-omeprazole comprising the desolvation of said methanol-solvated magnesium salt of S-omeprazole.
 14. A process according to claim 13, wherein the methanol-solvated magnesium salt of S-omeprazole has an X-ray diffractogram that comprises characteristic peaks at approximately 5.6; 6.5; 7.3; 8.0; 10.8; 12.6; 13.8; 14.7; 16.8; 17.5; 17.8; 19.1; 19.6; 20.1; 20.4; 22.1; 23.4; 24.2; 25.2 degrees 2 theta.
 15. A process according to claim 13, wherein the desolvation comprises the operations of: suspension of the magnesium salt of S-omeprazole in water; isolation of the magnesium salt of S-omeprazole obtained; and subsequent drying.
 16. A process according to claim 13, wherein the desolvation carried out by drying at a temperature of between about 60° C. to about 120° C.
 17. A process according to claim 13, wherein the solid form of methanol-solvated magnesium salt of S-omeprazole is previously prepared by a process comprising the following operations: a) crystallizing said magnesium salt of S-omeprazole from a solution of a magnesium salt of S-omeprazole in a solvent system that comprises a mixture of methanol/water with an amount of water about equal to or greater than about 0.01 ml/g of the magnesium salt of S-omeprazole starting material; b) isolating the magnesium salt of S-omeprazole that appears in the prior operation; and c) drying the magnesium salt of S-omeprazole obtained at a temperature less than about 60° C.
 18. A process according to claim 17, wherein the amount of water is between about 0.01 and about 4 ml/g of the magnesium salt of S-omeprazole starting material.
 19. A process according to claim 18, wherein the amount of water is between about 0.01 and about 2 ml/g of the magnesium salt of S-omeprazole starting material.
 20. A process according to claim 19, wherein the amount of water is between about 0.01 and about 0.5 ml/g of the magnesium salt of S-omeprazole starting material.
 21. A process according to claim 20, characterized by the amount of water being comprised between about 0.01 and about 0.1 ml/g of the magnesium salt of the S-omeprazole starting material.
 22. A process according to claim 17, wherein the drying temperature is about room temperature.
 23. A process according to claim 17, characterized by the additional step of adding a cosolvent selected from the group consisting of (C₁-C₄)-alkyl esters, ethyl acetate and acetonitrile to the solution of the magnesium salt of S-omeprazole in methanol/water.
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. A pharmaceutical composition comprising a therapeutically effective amount of the solid form of the magnesium salt of S-omeprazole as defined in claim 1, together with appropriate quantities of pharmaceutically acceptable excipients or carriers. 